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Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects
H Nishigori1, H Tomura, N Tonooka
1Laboratories of Molecular Genetics and Cell Physiology, Department of Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan.
Abstract:
Mutations in several genes encoding transcription factors of the hepatocyte nuclear factor (HNF) cascade are associated with maturity-onset diabetes of the young (MODY), a monogenic form of early-onset diabetes mellitus. The ability of the orphan nuclear receptor small heterodimer partner (SHP, NR0B2) to modulate the transcriptional activity of MODY1 protein, the nuclear receptor HNF-4alpha, suggested SHP as a candidate MODY gene. We screened 173 unrelated Japanese subjects with early-onset diabetes for mutations in this gene and found five different mutations (H53fsdel10, L98fsdel9insAC, R34X, A195S, and R213C) in 6 subjects as well as one apparent polymorphism (R216H), all present in the heterozygous state. Interestingly, all of the subjects with the mutations were mildly or moderately obese at onset of diabetes, and analysis of the lineages of these individuals indicated that the SHP mutations were associated with obesity rather than with diabetes. Therefore, an additional group of 101 unrelated nondiabetic subjects with early-onset obesity was screened for mutations in the SHP gene. Two of the previously observed mutations (R34X and A195S) and two additional mutations (R57W and G189E) were identified in 6 subjects, whereas no mutations were identified in 116 young nondiabetic lean controls (P = 0.0094). Functional studies of the mutant proteins show that the mutations result in the loss of SHP activity. These results suggest that genetic variation in the SHP gene contributes to increased body weight and reveal a pathway leading to this common metabolic disorder in Japanese.
Insights
Genetic variations in the small heterodimer partner (SHP) gene are linked to obesity in Japanese individuals. These SHP gene mutations lead to a loss of function, contributing to increased body weight and a common metabolic disorder.
Area of Science:
- Genetics
- Endocrinology
- Metabolic Disorders
Background:
- Mutations in hepatocyte nuclear factor (HNF) cascade genes are linked to maturity-onset diabetes of the young (MODY).
- Small heterodimer partner (SHP, NR0B2), a nuclear receptor, modulates HNF-4alpha activity, suggesting its role in MODY.
Purpose of the Study:
- To investigate mutations in the SHP gene as a potential cause of early-onset diabetes and obesity in Japanese subjects.
- To determine if SHP gene variations are associated with obesity independently of diabetes.
Main Methods:
- Screening of 173 unrelated Japanese subjects with early-onset diabetes for SHP gene mutations.
- Screening of 101 unrelated non-diabetic obese Japanese subjects for SHP gene mutations.
- Functional studies of mutant SHP proteins to assess their activity.
Main Results:
- Five different heterozygous SHP mutations were identified in 6 diabetic subjects.
- SHP mutations were found to be associated with obesity rather than diabetes in the initial cohort.
- Two previously identified and two new SHP mutations were found in 6 obese non-diabetic subjects, with no mutations in lean controls (P = 0.0094).
- Functional studies confirmed loss of SHP activity in mutant proteins.
Conclusions:
- Genetic variations in the SHP gene contribute to increased body weight in the Japanese population.
- SHP gene mutations represent a potential pathway leading to obesity, a common metabolic disorder.